Acetaminophen

Base Information

• Chemical Name: Acetaminophen
• CAS No.: 103-90-2
• Deprecated CAS: 8055-08-1,719293-04-6,1430221-00-3,719293-04-6
• Molecular Formula: C8H9NO2
• Molecular Weight: 151.165
• Hs Code.: 2924.29
• European Community (EC) Number: 203-157-5
• ICSC Number: 1330
• NSC Number: 755853,109028,3991
• UNII: 362O9ITL9D
• DSSTox Substance ID: DTXSID2020006
• Nikkaji Number: J4.025H
• Wikipedia: Paracetamol,Acetaminophen
• Wikidata: Q57055,Q83003217
• NCI Thesaurus Code: C198
• RXCUI: 161
• Pharos Ligand ID: W4WH4FK6P232
• Metabolomics Workbench ID: 37895
• ChEMBL ID: CHEMBL112
• Mol file: 103-90-2.mol

Synonyms:Acamol;Acephen;Acetaco;Acetamidophenol;Acetaminophen;Acetominophen;Algotropyl;Anacin 3;Anacin-3;Anacin3;APAP;Datril;Hydroxyacetanilide;N-(4-Hydroxyphenyl)acetanilide;N-Acetyl-p-aminophenol;p-Acetamidophenol;p-Hydroxyacetanilide;Panadol;Paracetamol;Tylenol

Chemical Property of Acetaminophen

Chemical Property:

• Appearance/Colour: White crystalline powder
• Vapor Pressure: 0.008Pa at 25℃
• Melting Point: 168-172 °C(lit.)
• Refractive Index: 1.619
• Boiling Point: 387.8 °C at 760 mmHg
• PKA: 9.86±0.13(Predicted)
• Flash Point: 188.4 °C
• PSA: 49.33000
• Density: 1.249 g/cm³
• LogP: 1.42360
• Storage Temp.: Store at RT
• Solubility.: ethanol: soluble0.5M, clear, colorless
• Water Solubility.: 14 g/L (20 ºC)
• XLogP3: 0.5
• Hydrogen Bond Donor Count: 2
• Hydrogen Bond Acceptor Count: 2
• Rotatable Bond Count: 1
• Exact Mass: 151.063328530
• Heavy Atom Count: 11
• Complexity: 139

Purity/Quality:

99% ^*data from raw suppliers

Acetaminophen ^*data from reagent suppliers

Safty Information:

• Pictogram(s): Xn
• Hazard Codes: Xn,T,F
• Statements: 22-36/37/38-52/53-36/38-40-39/23/24/25-23/24/25-11
• Safety Statements: 26-36-61-37/39-22-45-36/37-16-7

MSDS Files:

SDS file from LookChem

Useful:

• Chemical Classes: Other Uses -> Pharmaceuticals
• Drug Classes: Nonsteroidal Antiinflammatory Drugs
• Canonical SMILES: CC(=O)NC1=CC=C(C=C1)O
• Recent ClinicalTrials: Assess the Safety, Tolerability, and Pharmacokinetics of AZD6234 Following Single Ascending Dose Administration to Healthy Subjects Who Are Overweight or Obese
• Recent EU Clinical Trials: A Phase III Prospective, Randomized, Multicenter, Double-Blind, Placebo-controlled clinical study to evaluate the efficacy and safety of fixed dose combination (FDC) product Ibuprofen/Paracetamol/Phenylephrine Hydrochloride 200 mg/500 mg/10 mg film-coated tablets (containing Ibuprofen 200 mg, Paracetamol 500 mg and Phenylephrine Hydrochloride 10 mg) compared to Doregrippin? 500 mg/10 mg film-coated tablets (containing Paracetamol 500 mg and Phenylephrine Hydrochloride 10 mg) and Nurofen? 200 mg Tablets (containing Ibuprofen 200 mg) for the temporary relief of cold and flu symptoms, i.e. mild to moderate pain, sore throat, fever and nasal congestion.
• Recent NIPH Clinical Trials: The comparison of post operative pain control between intravenous patient-control-analgesia and acetaminophen -a randomized controlled study-
• Inhalation Risk: A nuisance-causing concentration of airborne particles can be reached quickly.
• Effects of Long Term Exposure: Ingestion may cause effects on the kidneys and liver. This may result in impaired functions.
• Commonly Used Analgesic: Acetaminophen is widely used to alleviate both acute and chronic pain, making it one of the most commonly used analgesic agents.
• Safety Profile: Acetaminophen is considered safe for use in patients for whom non-steroidal anti-inflammatory drugs (NSAIDs) are contraindicated, such as those with gastric ulcers, bronchial asthma, pregnant women, nursing mothers, and children.
• Mechanism of Action: Initially believed to induce analgesia by inhibiting the enzyme cyclooxygenase (COX), it is now understood that acetaminophen is metabolized to p-aminophenol, which crosses the blood-brain barrier and is further metabolized to N-acylphenolamine (AM404). AM404 acts on transient receptor potential vanilloid 1 (TRPV1) and cannabinoid 1 (CB1) receptors in the midbrain and medulla, which are co-localized mediators of pain modulation.
• Absence of Anti-inflammatory Activity: Unlike NSAIDs, acetaminophen does not possess anti-inflammatory activity, as it is a weak inhibitor of COX and does not inhibit neutrophil activation. Therefore, it is not suitable for treating inflammatory pain conditions.
• Historical Background: Paracetamol (acetaminophen) was first synthesized in 1893 and gained popularity as an analgesic and antipyretic drug after the decline in the use of phenacetin due to serious side effects. It became freely available in the 1950s and is now widely used for the treatment of mild to moderate pain and fever.
• Metabolism and Analgesic Effects: Acetaminophen is metabolized to p-aminophenol, which is converted to AM404 by fatty acid amide hydrolase. Another pathway involves the formation of N-acetyl-p-benzoquinoneimine (NAPQI), which also produces analgesia by activating transient receptor potential ankyrin 1 receptors. However, AM404 is considered the most important mediator of acetaminophen-induced analgesia, acting on TRPV1 receptors in the brain.
• Central Effect: Acetaminophen exhibits a "central" effect due to its action on TRPV1 and CB1 receptors in the brain, which are considered the main mediators of acetaminophen-induced analgesia.

Technology Process of Acetaminophen

There total 193 articles about Acetaminophen which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 85.0%

4-Hydroxyacetophenone (99-93-4) → N-Methyl 4-hydroxy benzamide (27642-27-9) + 4-acetaminophenol (103-90-2,8055-08-1) + 4-hydroxyacetophenone oxime (34523-34-7)

Guidance literature:

With hydroxylamine sulfate; at 80 ℃; for 2.5h;

DOI:10.1021/jo00098a050

Reference yield: 75.6%

N-Phenylacetohydroxamic acid (1795-83-1) → N-(2-chlorophenyl)acetamide (533-17-5) + 4-acetaminophenol (103-90-2,8055-08-1) + N-(4-chlorophenyl)acetamide (539-03-7) + 2-(acetylamino)phenol (614-80-2)

Guidance literature:

With tetrachloromethane; tributylphosphine; In acetonitrile; for 41h; Ambient temperature;

DOI:10.1246/cl.1993.1369

Reference yield: 27.0%

Acetanilid (103-84-4) → 4-acetaminophenol (103-90-2,8055-08-1) + 2-(acetylamino)phenol (614-80-2) + meta-hydroxyacetanilide (621-42-1)

Guidance literature:

With dihydrogen peroxide; at -40 ℃; for 0.5h; Product distribution; HF - SbF₅;

upstream raw materials:

4-nitro-phenol

1-(4-hydroxy-phenyl)-ethanone-hydrazone

mercapto-acetic acid-(4-hydroxy-anilide)

acetic anhydride

Downstream raw materials:

2-[4-(acetylamino)phenoxy]ethanol

N-(4-Hydroxy-3-piperidinomethylphenyl)acetamid

4-acetamido-α-(N-morpholino)-o-cresol

acetic acid-{4-[2-hydroxy-3-(2-hydroxy-ethoxy)-propoxy]-anilide}

Refernces

Convergent Versus Divergent Three-Step Synthesis of the First (4-Aminophenoxy)alkanoic Acid-Based Tripodal Melamines

10.1080/00397911.2015.1041048

The research details the convergent versus divergent three-step synthesis of the first (4-aminophenoxy)alkanoic acid-based tripodal melamines. The study aimed to develop novel tripodal N-substituted melamines as s-triazine derivatives, which have potential applications in the construction of luminescent enantiomorphic three-dimensional metal-organic frameworks. The researchers compared two synthetic routes, starting from either N-(4-hydroxyphenyl)acetamide (Paracetamol) for the convergent approach or cyanuric chloride with 4-aminophenol for the divergent approach. Key chemicals used in the process included Paracetamol, cyanuric chloride, 4-aminophenol, ethyl bromoacetate, and various reagents for the hydrolysis and etherification steps. The conclusions highlighted that N-(4-hydroxyphenyl)acetamide was a promising starting material for the convergent synthesis of the novel tripodal melamines with overall yields of 76% for (4-aminophenoxy)acetic acid and 47% for 4-(4-aminophenoxy)butyric acid derivatives. The divergent approach yielded similar compounds with overall yields ranging between 36 and 48%. The crucial steps in both strategies were the Williamson etherification of N-masked forms of 4-aminophenol and the acidic hydrolysis of the (4-aminophenoxy)alkanoic segments during their N-, O-chemoselective deprotection.

Reaction of α-(n-alkylcarbonyloxy)alkyl (ACOA) halides with 4-hydroxyacetanilide and 2,2,5,7,8-pentamethyl-6-chromanol: The effect of steric hindrance on reaction path

10.1055/s-2007-1000858

The research study on the synthesis and alkylation of phenols with α-(n-alkylcarbonyloxy)alkyl (ACOA) halides, focusing on the impact of steric hindrance on the reaction path. The experiments involved the synthesis of ACOA iodides and their subsequent reaction with 4-hydroxyacetanilide (acetaminophen, APAP) and 2,2,5,7,8-pentamethyl-6-chromanol, a sterically hindered phenol. The aim was to determine if steric hindrance affected the ratio of acylated to alkylated products. Various reaction conditions were tested to maximize the yield of the desired alkylated product. The reactants included different ACOA halides with varying alkyl chain lengths and phenols with different steric hindrance. The analyses used to determine the product distribution included 1H NMR spectroscopy and melting point determination, with purification methods involving column chromatography and crystallization. The study found that steric hindrance was not a significant factor in the reaction outcomes, suggesting that n-alkyl ACOM and ACOA promoieties could be viable alternatives to pivalate-based derivatives, which are associated with toxicity.